It was estimated by the National Cancer Institute (NCI) that 1,529,560 new cases of cancer of all types would occur in 2010 and 569,490 deaths were statistically projected for the same year in the United States. Most solid tumors are uniformly fatal once they have disseminated beyond their tissue of origin. The efficacy of current cancer chemotherapy is limited by systemic toxicity and lack of tumor selectivity, resulting in a variety of side effects. Thus, there is a need to develop cancer-specific agents for the treatment of both metastatic and non-metastatic cancers.
Emetine is a natural product alkaloid found in the root of Psychotria ipecacuanha. Emetine has been shown to possess anti-cancer activities via what are believed to be a variety of mechanisms of action. Emetine is an inhibitor of mitochondrial and ribosomal protein synthesis and also interferes with the synthesis and activities of DNA and RNA. Emetine has a very significant anti-cancer potency and its chemotherapeutic action was evaluated up to Phase II clinical trials on several solid tumors about four decades ago. However, it was found that emetine has a very narrow therapeutic index and can cause side effects like muscle fatigue and cardiac toxicity.
It has been reported that N-(2-hydroxypropyl)-methacrylamide (HPMA) copolymer conjugates containing emetine were 60 times less toxic than free emetine in B16F 10 melanoma cells and 225 times less toxic in L1210 leukemia cells. It was also reported that the prodrug positively affected the survival of animals with L1210 tumors. However, the prodrug polymer was found to only contain about 8% (wt/wt) of bound emetine and did not significantly affect the rate of tumor growth. These findings discouraged further development of emetine into a clinically useful anticancer drug.